Methods for enhancing wound healing

ABSTRACT

A method for treating a patient having a wound is described. The method includes administering an amount of a chemodenervating agent such that healing of the wound is enhanced. The method is illustrated by detailing the mean differences of the scores of the paired experimental and control scars across three observers.

TECHNICAL FIELD

The invention relates to a method for enhancing wound healing.

BACKGROUND OF THE INVENTION

Immobilization is a basic therapeutic principle in wound healing, commonto the treatment of lesions of all kinds. Casts, plates, and suturesminimize the negative effects of muscle tension on healing tissues.Since tension is one of the chief factors determining the degree of scarformation, this principle also holds true in skin lesions. Thecarefully-planned execution of an elective skin incision frequentlyachieves the best aesthetic result.

Surgeons have been seeking techniques and methods to reduce excessivescar formation, especially in the face. Many approaches have beenundertaken to overcome the negative influence of muscular tension on thewound healing process, including various suture techniques, steroidinjections, undermining wound edges, and placing incisions in a lineparallel to relaxed skin tension lines (RSTLs).

The etiology of skin tension lines, first described more than a centuryago, has been subject to controversy over the years. There is generalagreement, however, that skin tension lines influence the healing ofincisions according to their relative positions. There is evidence thatthe formation of RSTLs is a dynamic process over time. Studies on fetalcalves and human fetal skin suggest that RSTLs are not geneticallydetermined, but represent a change of texture of the skin secondary toextrinsic and/or intrinsic forces. Lorenz, H. P. et al., Development,114 (1):253-259, (1992). This change in texture gives skin certainmechanical characteristics that are retained even when excised. Muscletension is thought to be a major factor in the formation of RSTLs.

Increased skin tension has a negative effect on wound healing, causinghypertrophic scars or wound dehiscence. See, for example, Sherris, D. A.et al., Otolaryngologic Clinics of North America, 28(5):1957-1968, 1995.Repeated microtrauma, caused by continuous displacement of injuredtissue, induces a prolonged inflammatory response and an increasedmetabolic activity during the healing process. As a consequence,extracellular deposition of collagen and glycosaminoglycans canintensify and lead to hypertrophic scars. The incidence of hypertrophicscars is higher in certain anatomic areas where there is increasedmuscular movement. McCarthy, J. G., Plastic Surgery, 1990, Vol. 1,Philadelphia, W B Saunders, page 44.

SUMMARY OF THE INVENTION

The invention is based, in part, on a new therapy for management of bothtraumatic and iatrogenic wounds, which includes the elimination of thetension acting on the wound. The new therapy includes injection of achemodenervating agent to paralyze muscles capable of exerting tensionon such wounds, providing better wound healing with minimal scardevelopment. In addition, early immobilization in elective proceduresalso allows a surgeon to use finer sutures, further improving thecosmetic result.

In one aspect, the invention features a method for treating a patienthaving a wound (e.g., a facial wound). The method includes locallyadministering an amount of a chemodenervating agent such that healing ofthe wound is enhanced. The chemodenervating agent can be, for example, abotulinum toxin, saxitoxin, tetanus toxin, or tetrodotoxin, and istypically administered by injection. The botulinum toxin can bebotulinum toxin A, B, C, D, E, F, or G, and in particular botulinumtoxin A or B. The method further can include administering an amount ofa local anesthetic agent and/or a local vasoconstrictive agent effectiveto enhance wound healing. Local anesthetic agents such as lidocaine,bupivacaine, or mepivacaine, or local vasoconstrictive agents can beadministered prior to injection with the chemodenervating agent orsimultaneously with the chemodenervating agent.

A composition having a chemodenervating agent, a local anesthetic, and alocal vasoconstrictive agent also is featured.

In another aspect, the invention features an article of manufacture thatincludes packaging material and an amount of a chemodenervating agent.The packaging material includes a label that indicates thechemodenervating agent is useful for treating a patient having a wound.Administration of the chemodenervating agent enhances healing of thewound. The chemodenervating agent can be a botulinum toxin such asbotulinum toxin A. The article of manufacture also can include a localanesthetic agent or a vasconstrictive agent.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used to practicethe invention, suitable methods and materials are described below. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph that indicates the mean differences of the scores ofthe paired experimental and control scars across three observers.

DETAILED DESCRIPTION

As described herein, the cosmetic appearance of a scar is influenced byunderlying muscle activity during the wound healing process. Paralysisof the underlying muscle activity increases the rate of healing andyields a better cosmetic result. Without being bound by a particularmechanism, locally induced paralysis of the musculature subjacent to acutaneous defect is thought to minimize the repetitive tensile forces onthe wound edges, resulting in superior cosmetic outcome in the resultantscar.

Thus, the invention provides a method for treating a patient having awound that includes locally administering an amount of achemodenervating agent effective to enhance wound healing in thepatient. As used herein, “chemodenervating agent” refers to any agentthat interrupts nerve impulse transmission across the neuromuscularjunction, blocks the release of neurotransmitters, or alters the actionpotential at the voltage gated sodium channel of neurons, sufficient toreduce tension within muscles in and near a wound site. As used herein,“wound” refers to skin, tendon, or bone wounds, and can includeinflammatory lesions or other lesions adversely affected by muscletension or movement. Skin wounds include, for example, faciallacerations such as those introduced by trauma (i.e., a car accident),or iatrogenic, such as surgically introduced incisions. In particular,surgically introduced incisions include scar revision excision surgery.As such, a skin wound includes elective incisions and nonelectiveincisions. Skin wounds may be relatively favorable or unfavorable. Asused herein, “favorable wound” refers to an incision or laceration thatis relatively parallel to RSTLs, whereas “unfavorable wound” refers toan incision relatively perpendicular to RSTLs. Both favorable andunfavorable wounds benefit from the methods described herein. Tendonwounds include, for example, ruptured or injured tendons and tendinitis.

Bone wounds include favorable and unfavorable fractures. A “favorablefracture” refers to a fracture that is not prone to displacement of oneor more fragments of the fracture by muscle pull, whereas an“unfavorable fracture” refers to a fracture that is prone todisplacement of one or more fragments by muscle pull. The treatment fora fracture can be facilitated if muscle tension on the affected fractureis minimized. Thus, the treatment becomes less invasive, less timeconsuming and/or less costly. For example, with a fractured elbow, thetriceps muscle can displace the bone fragments. An alternative tosurgical repair includes use of percutaneous wires to hold the bones inplace, and relaxation of the triceps muscle by paralysis with achemodenervating agent. Use of wires and a chemodenervating agent mayreduce or avoid surgery and/or the accompanying general anesthesia.

The methods described herein enhance wound healing by minimizing theadverse effect of muscle tension and movement on the wound, as well asimproving cosmetic appearance through reduced scar development. Inaddition, inflammation may be reduced during the healing process.

Chemodenervating Agents

Non-limiting examples of chemodenervating agents include botulinumtoxin, saxitoxin, tetanus toxin, and tetrodotoxin. Suitable botulinumtoxins include, for example, botulinum toxins A, B, C (C1 and C2), D, E,F, or G. Botulinum toxins A, B, and F are particularly useful. Botulinumtoxin A is a potent drug that produces temporary muscular paralysis wheninjected locally. Botulinum toxin A has been used in the treatment of awide range of disorders associated with involuntary muscle contraction.It has been demonstrated to be effective in treating focal dystoniassuch as blepharospasm, nondystonic disorders such as hemifacial spasms,disorders of conjugate eye movement such as strabismus and nystagmus,spasticity disorders such as multiple sclerosis and cerebral palsy, andfor disorders of localized muscle spasm. In addition, botulinum toxin Ahas been used to treat age related rhytids of the upper face. Botulinumtoxin A is safe and effective to use, and is relatively painless withrare side effects characterized as mild and transient. Onset of actiontakes place within 24 to 72 hours after injection and lasts 2 to 6months. Botulinum toxin A is available commercially, e.g. from Allergan,Inc. (Irvine, Calif., Botox®) and Speywood Pharmaceuticals (England,Dysport®).

Dosages of botulinum toxin A required for local immobilization typicallydo not exceed 1 unit toxin per kg body weight and are safe. Primatestudies have indicated that no systemic effects are observed at dosagesbelow 33 units/kg body weight. See, for example, Scott and Suzuki, Mov.Disord., 1988, 3:333-335.

Botulinum toxins B and F also have been used for dystonia patients.Greene, P. E. et al., Mov. Disord., 1996, 11(2):181-184; and Truong, D.D. et al., Mov. Disord., 1997, 12(5):772-775. Botulinum toxin B isavailable from Elan Corporation (Dublin, Ireland, Neurobloc®).

Botulinum toxins also can be obtained by purifying the toxins fromstrains of Clostridium botulinum, using standard techniques. Forexample, botulinum toxin A can be produced in a Hall strain using anutritive medium containing casein digest, yeast extract, and dextrose.After lysis of the culture, the toxin is released into the medium andactivated by proteases, and then is acid precipitated. Furtherpurification can include extraction with a sodium phosphate buffer,ethanol precipitation, and crystallization in ammonium sulfate. See, forexample, Schantz, E. J. and Johnson, E. A., Microbiol. Rev., 1992,56(1):80-99.

Other chemodenervating agents such as saxitoxin, tetanus toxin, andtetrodotoxin are also suitable. The paralysis induced by saxitoxin,however, does not last as long as that induced by botulinum toxin.Consequently, repeated injections of saxitoxin may be needed. Saxitoxincan be purified by known procedures. See, for example, Schantz, E. J. etal., J. Am. Chem. Soc., 1975, 97:1238-1239. Tetanus toxin can decreaseacetylcholine release in cholinergic peripheral nerves when injectedlocally. Dreyer, F., Peripheral actions of tetanus toxin, p. 179-202,In: Botulinum neurotoxin and tetanus toxin. Academic Press, Inc., SanDiego. L. L. Simpson (ed.). Tetanus toxin also can enter the centralnervous system where it causes uncontrolled muscle spasms. When tetanustoxin is employed in the methods described herein, precautions must betaken to ensure local response. Matsuda, M. et al., Biochem. BiophysRes. Commun., 1982, 104:799-805; and Habermann, E. et al.,Naunyn-Schmiedeberg's Arch. Pharmacol., 1980, 311:33-40. Tetanus toxincan be purified by standard procedures. See, for example, Robinson, J.P., Methods Enzymol., 1988, 165:85-90. Tetrodotoxin blocks the sodiumchannel of excitable membranes of nerve and muscle tissues, and can bepurified using routine techniques. See, for example, Yotsu, M. et al.,Toxicon, 1987, 25:225-228.

Local administration of the chemodenervating agents typically occurs bysubcutaneous (SQ), intramuscular (IM), perimuscular injection, orpercutaneous instillation (e.g., air gun or skin patch). Whenchemodenervating agents are injected SQ, the agent reaches the muscle byperfusion. For elective incisions, the chemodenervating agent can beadministered prior to making an incision, while making an incision, orafter an incision has been made.

Administration of Local Anesthetics and Local Vasoconstrictive Agents

The method of treatment further can include administering either a localanesthetic agent or a local vasoconstrictive agent, or both. Such agentscan be administered prior to injection of the chemodenervating agent orsimultaneously with the injection of the chemodenervating agent. Localanesthetics block nerve conduction, and can cause sensory and motorparalysis in a localized area. Local anesthetics have a rapid onset ofaction, and therefore reduce muscle tension on the wound almostimmediately as well as reduce pain associated with the injection. Theextent of muscular paralysis achieved by a local anesthetic agent ishelpful in predicting the extent of paralysis that can be achieved bysubsequent injection of a chemodenervating agent into the same injectionsite. Thus, possible local side effects, such as diffusion of thechemodenervating agent to adjacent muscle groups, is prevented.Non-limiting examples of local anesthetic agents include lidocaine,bupivacaine, chloroporcaine etidocaine, or mepivacaine, and areavailable commercially. In addition, other amide types of localanesthetics can be used in the method. Suitable amounts of localanesthetics can be readily determined by a physician. For example, about1 to 5 mls of lidocaine at a concentration of about 0.5%-about 2% can beinjected. Administration of local anesthetics is particularly usefulwhen incisions are introduced surgically, such as during scar reversionexcision surgery.

Administration of a local vasoconstrictive agent results in a decreasedhemoperfusion of the injected tissue. Thus, administration of a localvasoconstrictive agent can help prevent or control diffusion of thechemodenervating agent and minimize possible side effects, such as browptosis or incomplete eye closure from injection into the frontalisand/or corrugator supercilii muscles. Non-limiting examples of localvasoconstrictive agents include epinephrine and phenylephrine, and areavailable commercially. A suitable amount of a local vasoconstrictiveagent can be readily determined by a physician. For example, 5 mls ofepinephrine 1:100,000 or 1:200,000 typically is used for localvasoconstrictive action.

Compositions containing a chemodenervating agent and a local anesthetic,and/or a local vasoconstrictive agent, can be produced for applicationsin which it is desired to introduce chemodenervating agents and one ormore other components simultaneously. Such compositions can be prepared,for example, by reconstituting a lyophilized component with a solutionof another component. For example, lyophilized botulinum toxin can bereconstituted in a solution containing a local anesthetic and a localvasoconstrictive agent, or in a solution containing either a localanesthetic or a local vasoconstrictive agent. A composition containinglidocaine and epinephrine is commercially available, for example, fromAstra. Typically, lidocaine is present at 0.5-2% and epinephrine ispresent at 1:100,000 to 1:200,000.

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

EXAMPLE 1 Enhanced Wound Healing by Injection of a ChemodenervatingAgent in Monkeys

In order to closely mimic the effects of muscle activity on human facialskin wounds, the use of an appropriate animal model was mandatory. Dueto extensive skin laxity and inadequate mimetic musculature, establishedmodels like rats, pigs, and horses, were not ideal for this purpose.Cynomolgus macaque monkeys (Macaca fascicularis) were chosen as a modelsince the anatomy of their cranio facial and cutaneous anatomy resemblesthat of humans.

The study was approved by the Institutional Committee of Animal Care andUse at the Mayo Clinic and the animals were housed, cared for, and fedin compliance with the institutional guidelines. No animal wassacrificed. All procedures were performed with anesthesia consisting ofKetamine at 20 mg/kg IM (Ketaset®, Fort Dodge), Xylazine at 0.5 mg/kg IM(Rompun®, Bayer), and Isoflurane at 1% (Isoflurane®, Abbott).

The forehead was chosen for the excision site in the monkeys as thefrontalis, procerus and corrugator supercilii muscles constantly exerttension on the forehead skin and paralysis of these muscles leads to nofunctional deficit. In order to minimize local variables, theexperimental and control excisions were each planned in symmetricanatomic location in the same individual animal. Three Y-shapedexcisions with their main axis perpendicular to the RSTLs were plannedsymmetrically in relation to the midline on each side of the forehead.

A template was used to determine the location and outline of theexcisions to ensure maximal precision. An experienced facial plasticsurgeon, blinded to the experimental conditions, performed allexcisions. Using standard surgical technique, the skin and subcutaneoustissue was excised and the frontalis muscle was preserved in the base ofthe defects. Subsequently, one side of the forehead was randomlydetermined as experimental and the mimetic musculature adjacent to eachexcision on that side was injected under direct vision with 7 units ofBotulinum Toxin A (Botox®, Allergan) in 0.9% saline (25 units/ml),resulting in a total dose of 21 units of Botulinum toxin A per halfforehead. The control side was injected in the same fashion with anequal volume of 0.9% saline alone. All wounds were closed with a single6-O Chromic Gut (Chromic Gut®, Ethicon) buried suture and multiple 5-Oblack monofilament Nylon (Ethilon®, Ethicon) superficial sutures. Fromthe third day postoperatively, marked paralysis of the Botulinum toxin Atreated side was observed in all six animals. Extraocular musclemovement and eyelid closure were not compromised.

Three experienced facial surgeons, who were not present during thesurgical procedures, were used as blinded observers to evaluate thecosmetic appearance of the scars at 1, 4, and 12 weeks postoperatively.Care was taken to sedate the animals deeply for each assessment so theevaluators were not able to recognize the paralyzed side of theforehead.

First, the evaluators were asked to score each single scar on a 10 cmvisual analogue scale. The 36 forehead scars (3 experimental scars and 3control scars per animal) were evaluated by each assessor independently.In this scale, scars were rated from 1 to 10, with 0 being the worst and10 being the best. At 1 and 4 weeks postoperatively, none of the blindedratings revealed a significantly better cosmetic appearance of theexperimental or the control wounds. The mean ratings of the threeassessors at 12 weeks postoperatively reached a higher score on theexperimental side in 16 of 18 of the symmetric pairs of scars (FIG. 1).The bars in FIG. 1 represent the mean differences of the scores of thepaired experimental and control scars across the three observers. Themean score by assessor #1 was 9.4 for the experimental scars and 8.1 forthe control scars; the mean score by assessor #2 was 8.0 for theexperimental scars and 7.3 for the control scars; and the mean score byassessor #3 was 7.9 for the experimental scars and 7.3 for the controlscars. The mean scores across the three assessors were 8.4 (SD 1.0) forthe experimental side and 7.6 (SD 0.9) for the control side. Thestatistical assessment of an intervention effect was based on using theaverage rating across the three evaluators and fitting a two-factor(intervention, site) repeated measures analysis of variance model,taking into account the correlation of measurements obtained on the sameanimal. Based on this analysis, the scars on the experimental side wererated significantly better than the scars on the control side (p<0.01).

Secondly, the assessors were asked to examine the groups of 3 scars oneither side of each animal's forehead (12 weeks postoperatively) and torate each scar as better, equal to, or worse than its symmetriccounterpart. A consensus score was derived from the majority of thevotes. The experimental sides were assessed as better than the controlsides in 6 of the 6 animals. Based on a two-tailed, one-sample binomialtest, this result was statistically significant (p<0.031) (Table 1).TABLE 1 Assessment of Scars Consensus Animal Assessor 1 Assessor 2Assessor 3 Score 1 + ? + + 2 + ? + + 3 + + − + 4 + + + + 5 + + + +6 + + + ++ = Assessment of experimental side as better− = Assessment of experimental side as worse? = Assessment of both sides equal

Representative sections of the scars were excised 12 weekspostoperatively, using a 4 mm punch. The biopsy specimens were embeddedin formalin, cut in 25 μm thick sections, and hematoxylin and Eosinstained for evaluation. Scars were classified as mature with no sign ofinflammation or ongoing remodeling.

EXAMPLE 2 Enhanced Wound Healing by Botulinum Toxin A Injection inHumans

A male patient (26 years of age, 82 kg) underwent scar revision excisionsurgery. The scar was located on the forehead approximately 2 cm lateralof the midline on the left, and approximately 3 cm cranial to the mostsuperior extension of the orbital rim. Its direction was horizontal,giving it a favorable position relative to the wrinkle lines. The scarwas a result of a trauma at age seven, and was closed at a tertiaryreferral center at the time.

The patient was placed in a supine position, and 5 ml of 0.5% lidocainewith 1:200,000 epinephrine was locally injected. The scar was excisedand bleeding was controlled with monopolar cautery. Botulinum toxin Awas injected (10 units) into the frontalis muscle under direct visionfanning out from the wound. The wound was closed using 6-0 Vicryl fordeep and 6-0 Nylon for superficial sutures. An additional 7.5 units ofbotulinum toxin A were injected into the procerus and corrugator musclesbilaterally, as frowning caused distortion of the wound.

Approximately 24 hours after surgery, the patient developed markedparalysis of the injection muscles, and had lost the ability to wrinklethe forehead skin in an area of about 4 cm in diameter around theexcision. The wound healed well in the early postoperative period. Itwas apparent that there was decreased movement and tension on the woundedges. The forehead wound of the patient healed without complications.Compared to the preoperative scar, the cosmetic appearance of theresulting scar 12 months postoperatively was excellent and superior tothe initial scar.

Example 3 Evaluation of Scars from Patients Injected with aChemodenervating Agent Alone or in Combination with a Local Anesthetic

Healthy volunteers were informed about potential risks and side effectsof the treatment. Formal written informed consent was obtained inaccordance with the Mayo Institutional Review Board regulations. Priorto enrollment in the study, symmetry of frontalis, procerus, andcorrugator supercilii function was assessed and subjects were onlyincluded in the study if there was no functional asymmetry present. Theforehead of the subjects was divided by the midline into two symmetricsides, one serving as the control and the other as the experiment side.The side of the forehead which was to serve as control was determinedrandomly, and was injected with Botulinum Toxin A (Botox) reconstitutedin 0.9% saline. The experimental side was injected with Botulinum ToxinA reconstituted in 1% or 2% lidocaine with 1:100,000 epinephrine. Thecombination of these agents with Botulinum toxin A was achieved byreconstituting 100 units of freeze dried Botulinum toxin A in 5 ml of 1%or 2% Lidocaine with 1:100,000 epinephrine solution (Xylocaine at 1% or2% with epinephrine 1:100,000, Astra). This resulted in a dosage whichis commonly utilized for each of these substances in routine clinicaluse (20 units Botulinum toxin per ml of 1% or 2% lidocaine with1:100,000 epinephrine).

In order to assure symmetry and equality of the injections, the sites ofinjection were predetermined with a template. A predetermined amount andvolume of toxin was injected into each location. After the injection,subjects were asked to evaluate the intensity of the pain resulting fromthe percutaneous injections for both sides of the forehead separately.This was done with a standardized questionnaire approximately 10 minutesafter the injection. The pattern of muscular paralysis achieved by thelocal anesthetic plus Botox was compared to the pattern of paralysisresulting from Botox A alone at one week after the injection. Thepotency and duration of action of Botox A reconstituted in thevasoconstrictive and anesthetic agent was compared to Botox Areconstituted in 0.9% saline by serial observation until the return offacial muscular function. Subjects were photographed 5-15 minutes afterinjection, one week after injection, and monthly thereafter attemptingmaximal forehead muscle contracture.

Two particular examples of such injections are provided. A white femalewas injected with 20 units Botox in 1 ml 1% lidocaine with 1:100,000epinephrine in the right side of the forehead and in exactly the samefashion with 20 units Botox, reconstituted in 0.9% saline in the leftside of the forehead. A second white female was injected in the samemanner, except that 2% lidocaine was used. Eight portions of 0.125 mlwere injected into each side of the forehead and the sites of injectionwere determined by a template. Each subject immediately developedparalysis of the frontalis, procerus, and depressor supercilii muscleson the right side of the forehead. The pattern and extent of immediatemuscular paralysis resulting from the immediate action of the localanesthetic drug (Lidocaine 1% or 2%) was predictable of the pattern andextent of delayed paralysis achieved by Botox one week later. The effectof the Botox-induced muscular paralysis faded in a symmetric fashion,indicating that the duration of Botox induced muscular paralysis was notaffected by the addition of Lidocaine or epinephrine.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1-31. (canceled)
 32. A method for treating a patient having a traumaticor an iatrogenic skin wound, said method comprising locallyadministering an amount of botulinum toxin to said skin wound, such thathealing of said skin wound is enhanced.
 33. The method of claim 32,wherein said botulinum toxin is selected from the group consisting ofbotulinum toxin A, B, C, D, E, F, and G.
 34. The method of claim 33,wherein said botulinum toxin is botulinum toxin A.
 35. The method ofclaim 33, wherein said botulinum toxin is botulinum toxin B.
 36. Themethod of claim 32, wherein said administering step is by injection. 37.The method of claim 36, wherein said botulinum toxin is subcutaneouslyinjected.
 38. The method of claim 36, wherein said botulinum toxin isintramuscularly injected.
 39. The method of claim 36, wherein saidbotulinum toxin is percutaneously instilled.
 40. The method of claim 32,said method further comprising administering a local anesthetic.
 41. Themethod of claim 40, wherein said local anesthetic is lidocaine.
 42. Themethod of claim 40, wherein said local anesthetic is bupivacaine. 43.The method of claim 40, wherein said local anesthetic is mepivacaine.44. The method of claim 40, wherein said local anesthetic isadministered prior to administration of said botilinum toxin.
 45. Themethod of claim 40, wherein said botulinum toxin and local anestheticare co-administered.
 46. The method of claim 32, said method furthercomprising administering a local vasoconstrictive agent.
 48. The methodof claim 46, wherein said local vasoconstrictive agent is epinephrine.49. The method of claim 32, said method further comprising administeringa local anesthetic and a local vasoconstrictive agent.
 50. The method ofclaim 49, wherein said local anesthetic and said local vasoconstrictiveagent are administered prior to said botulinum toxin.
 51. The method ofclaim 32, wherein said skin wound is a facial wound.
 52. The method ofclaim 32, wherein said skin wound is a surgically introduced incision.53. The method of claim 52, wherein said botulinum toxin is administeredprior to making said surgically introduced incision.
 54. The method ofclaim 52, wherein said botulinum toxin is administered while making saidsurgically introduced incision.
 55. The method of claim 52, wherein saidbotulinum toxin is administered after said surgically introducedincision has been made.
 56. The method of claim 51, wherein saidbotulinum toxin is administered so as to not compromise eyelid closure.57. The method of claim 32, wherein said skin wound is a favorablewound.
 58. The method of claim 32, wherein said skin wound is anunfavorable wound.
 59. The method of claim 32, wherein said skin woundcomprises subcutaneous tissue.
 60. The method of claim 32, wherein saidskin wound is a head wound.
 61. The method of claim 60, wherein saidhead wound is a forehead wound.
 62. The method of claim 60, wherein saidbotulinum toxin is administered to said head wound so as to notcompromise eyelid closure.
 63. The method of claim 32, wherein saidlocal administration comprises administration in or in close proximityto said skin wound.
 64. The method of claim 32, wherein said skin woundis the result of scar revision excision surgery.
 65. The method of claim32, wherein said local administration is in or in close proximity to amuscle selected from the group consisting of a frontalis muscle, aprocerus muscle, a corrugator muscle, and a depressor supercilli muscle.66. The method of claim 51 or 60, wherein said botulinum toxin isadministered so as to not compromise extraocular muscle movement.